Respiratory virus circulation during the first year of the COVID‐19 pandemic in the Household Influenza Vaccine Evaluation (HIVE) cohort

Abstract Background The annual reappearance of respiratory viruses has been recognized for decades. COVID‐19 mitigation measures taken during the pandemic were targeted at respiratory transmission and broadly impacted the burden of acute respiratory illnesses (ARIs). Methods We used the longitudinal Household Influenza Vaccine Evaluation (HIVE) cohort in southeast Michigan to characterize the circulation of respiratory viruses from March 1, 2020, to June 30, 2021, using RT‐PCR of respiratory specimens collected at illness onset. Participants were surveyed twice during the study period, and SARS‐CoV‐2 antibodies were measured in serum by electrochemiluminescence immunoassay. Incidence rates of ARI reports and virus detections were compared between the study period and a preceding pre‐pandemic period of similar duration. Results Overall, 437 participants reported a total of 772 ARIs; 42.6% had respiratory viruses detected. Rhinoviruses were the most frequent virus, but seasonal coronaviruses, excluding SARS‐CoV‐2, were also common. Illness reports and percent positivity were lowest from May to August 2020, when mitigation measures were most stringent. Seropositivity for SARS‐CoV‐2 was 5.3% in summer 2020 and increased to 11.3% in spring 2021. The incidence rate of total reported ARIs for the study period was 50% lower (95% CI: 0.5, 0.6; p < 0.001) than the incidence rate from a pre‐pandemic comparison period (March 1, 2016, to June 30, 2017). Conclusions The burden of ARI in the HIVE cohort during the COVID‐19 pandemic fluctuated, with declines occurring concurrently with the widespread use of public health measures. Rhinovirus and seasonal coronaviruses continued to circulate even when influenza and SARS‐CoV‐2 circulation was low.


| BACKGROUND
The annual reappearance of influenza has been recognized for decades through clinical identification and systematic surveillance of influenza-like illnesses. 1,2 The addition of molecular-based testing to clinical and public health surveillance systems has established patterns of seasonality for non-influenza viruses, as well. While specific timing and intensity can vary, broader patterns for specific viruses are remarkably predictable from year to year, with respiratory syncytial virus, influenza, coronaviruses, and human metapneumovirus increasing in the winter and parainfluenza increasing in the fall and/or spring. 3 Rhinoviruses are detected year-round, but increases in spring and fall are typical. 4 [10][11][12][13] The study conducted active surveillance for ARIs among cohort enrollees during the COVID-19 pandemic once new strategies to collect specimens were implemented according to SARS-CoV-2 transmission-control restrictions. 14 Here, we report changes to the circulation of respiratory viruses throughout multiple early waves of the pandemic in a cohort of households reporting high levels of COVID-19 mitigation practices with repeated serosurveys for the acquisition of SARS-CoV-2 antibodies.

| Study population
HIVE is a longitudinal cohort that has followed approximately 300-400 households per year in southeastern Michigan since 2011 using active surveillance for ARI. Methods for recruitment of participants and participation in the HIVE study have been previously described. 10 Eligible households must have ≥3 persons living at the same address with at least one child aged <10 years at the time of initial enrollment.
In mid-2020, eligibility was expanded to those with at least one child

| Mitigation survey
Adults from participating households were surveyed from July-August 2020 and May-July 2021 on COVID-19 mitigation practices.
The first survey included questions to assess changes in work and school attendance outside of the home, sources of trusted information, essential worker status, and common mitigation practices (e.g., masking, distancing, hand hygiene, etc.) (Supporting Information).
The second survey included additional questions regarding COVID-19 vaccination (Supporting Information).

| Population, illness, and infection characteristics
A total of 1606 individuals who were enrolled in the HIVE study contributed 23,502 person-months of follow-up during the study period.
Participants included 740 adults and 866 children in 402 households.
Most participants lived in households with two adults (n = 1281, 79.8%) and two children (n = 759, 47.3%) ( Table 1). The number of adults in a household ranged from 1 to 6, and the number of children ranged from 0 to 7 (data not shown).

| SARS-CoV-2 serology
Blood specimens were collected from 409 subjects from March

| DISCUSSION
The presented study, which began before the COVID-19 pandemic, offered an opportunity to observe the occurrence and patterns of circulating respiratory viruses during the first year of the pandemic.
Rhinovirus infections were detected throughout the study period.
Seasonal coronaviruses were detected in the winter months; only sporadic influenza, RSV, and SARS-CoV-2 detections were made during this time in the study area. Surveillance reports of ARI and detected viral infections within study participants increased after the statewide "Stay Home, Stay Safe" mandate ended. In contrast, ARI incidence in the cohort was higher between fall 2020 and winter 2021 (i.e., when respondents reported less adherence to mitigation practices relative to summer of 2020). Seroprevalence of SARS-CoV-2 antibodies was low throughout the study period.
Many of the non-pharmaceutical interventions deployed worldwide at the beginning of the COVID-19 pandemic were originally developed as a strategy for early reduction of peak transmission levels during an influenza pandemic, so the reduction in the circulation of many non-SARS-CoV-2 respiratory viruses was concurrent to the adoption of mitigation and continued high levels of influenza vaccination in the study participants was not surprising. [15][16][17][18] However, as influenza pandemics pass through communities in a matter of months, the maintenance of these measures over longer periods during multiple waves of COVID-19 may have disrupted the seasonality of other respiratory viruses to a degree never before seen. [19][20][21][22] The mechanism for the disruption of seasonal respiratory viruses by SARS-CoV-2 circulation-whether via non-pharmaceutical mitigation or an interference effect-remains unclear. One hypothetical mechanism is a biological interference between SARS-CoV-2 and other respiratory viruses, which has been observed in animal models and is presumed to occur on the population scale. [23][24][25][26][27] Crucially, it is likely that social and behavioral factors have played a significant role in these patterns, particularly the coinciding occurrence of such stark mitigation measures during this time (e.g., school and business closures and regional travel restrictions). These major alterations in contact patterns must be considered in conjunction with any biological hypotheses.
Rhinovirus was the most common respiratory virus detected in participant specimens and was detected throughout the study.

ACKNOWLEDGMENTS
We are grateful for the participants who contributed to the HIVE study.

CONFLICT OF INTEREST STATEMENT
ETM reports grant funding from Merck outside of the submitted work.

PATIENT CONSENT
All patients consented to participate in the study.

DISCLAIMER
The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.

DATA AVAILABILITY STATEMENT
No material has been used from other sources. All data associated with the study will be available upon request.

ETHICS STATEMENT
The University of Michigan Institutional Review Board gave ethical approval for this work.